The central hypothesis being tested in this proposal is that anticoagulant aptamers and their antidotes represent a safe and effective means of controlling coagulation and preventing thrombosis. In the previous funding cycle of this grant, we tested the hypothesis that aptamers are a class of compounds whose activity can be readily reversed by antidotes. We determined that this hypothesis is correct and in the process developed aptamers that can inhibit the activity of several coagulation factors including factors VIIa, IXa, Xa and thrombin, and generated two classes of antidotes, oligonucleotide-based antidotes and universal antidotes, that can rapidly reverse the anticoagulant activity of such aptamers. Furthermore, we also generated aptamer-antidote pairs against the platelet proteins GP IIb/IIIa and VWF and have demonstrated their ability to inhibit platelet function. Thus we now have a set of novel antidote-controllable anticoagulant agents that we will use in this proposal to test the overall hypothesis that such aptamers and antidotes represent a safe and effective approach to control coagulation and platelet function in a variety of clinically relevant settings. Such control is especially valuable in the case of anticoagulant therapy because administration of such therapeutics can induce side effects such as severe bleeding that increase patient morbidity and mortality. Our three specific aims are: 1) to elucidate the mechanism(s) that aptamers utilize to inhibit coagulation factor activity. 2) To assess the net therapeutic benefit of aptamers that inhibit safe anticoagulant targets versus aptamer-antidote pairs that reversibly inhibit validated anticoagulant targets. 3) To determine which anticoagulant aptamers can effectively inhibit coagulation in the setting of cardiopulmonary bypass surgery and determine if oligonucleotide and universal antidotes can rapidly and safely reverse the effects of such aptamers following surgery.